Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid

Definitions

• This invention relates to a novel nitrosourea compound and a process for preparing the same. More particularly, it relates to a compound of the formula: ##STR2## wherein R 1 is lower alkoxy, lower alkoxy-methoxy or 2-hydroxyethoxy, R 2 is aldo-pentofuranosyl, aldo-pentopyranosyl, aldohexopyranosyl or O-aldo-hexopyranosyl-(1 ⁇ 4)-aldo-hexopyranosyl, and A is straight or branched alkylene of one to four carbon atoms (said alkylene being optionally substituted with lower alkoxy).
• the nitrosourea compound [I] of the present invention shows potent anti-tumor or anti-leukemic activity and is useful to inhibit the growth of malignant tumor cells in warm-blooded animals.
• the anti-tumor effects upon leukemia is estimated by administering such drugs intraperitoneally to tumor cell-inoculated mice (i.e., mice implanted with tumor cells of Leukemia L-1210) for five consecutive days, 1-(2-chloroethyl)-1-nitroso-3-(2-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea at the daily dose of 0.5 mg/kg or 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-(L-arabinopyranosyl)urea at the daily dose of 0.45 mg/kg shows an increase of about 30% in the average life span of said mice.
• the nitrosourea compound [I] of the present invention is characterized by its great safety for use as an anti-tumor agent.
• the therapeutic index is estimated by the ratio of the optimal dose (the daily dose at which the maximum increase in the life span of tumor cell-inoculated mice occurs) to ILS 30 (the minimum daily dose which shows an increase of 30% in the life span of said mice) in case of Leukemia L-1210, said therapeutic indexes of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-[O- ⁇ -D-glucopyranosyl-(1 ⁇ 4)-D-glucopyranosyl]urea,1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea and 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-
• the compound [I] may also show an excellent therapeutic index estimated in terms of ratio of M.T.D. (the maximum tolerated dose which shows 100% inhibition for the growth of Ehrlich ascites tumor in mice without causing the death of said mice) to M.E.D. (the minimum effective dose which shows 100% inhibition for the growth of said ascites tumor).
• said therapeutic indexes (M.T.D./M.E.D.) of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-[O- ⁇ -D-glucopyranosyl-(1 ⁇ 4)-D-glucopyranosyl]-urea, 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea and 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(D-arabinopyranosyl)urea are 4 times greater than that of GANU.
• representative examples of the group R 1 include lower alkoxy such as methoxy, ethoxy and propoxy; lower alkoxy-methoxy such as methoxymethoxy and ethoxymethoxy; and 2-hydroxyethoxy.
• representative examples of the group A include straight or branched alkylene such as methylene, ethylene, propylene, butylene, 1-methylethylene, 1-ethylethylene, 2-methylethylene and 2-ethylethylene; and lower alkoxy-substituted alkylene such as 2-methoxyethylene, 2-ethoxyethylene, 2-methoxypropylene and 2-ethoxypropylene.
• a preferred subgenus includes the compound of the formula [I] in which R 2 is D-ribofuranosyl, L-arabinopyranosyl, D-arabinopyranosyl, D-xylopyranosyl, D-glucopyranosyl, D-galactopyranosyl, D-mannopyranosyl or O- ⁇ -D-glucopyranosyl-(1 ⁇ 4)-D-glucopyranosyl.
• R 1 is alkoxy of one or two carbon atoms
• R 2 is D-ribofuranosyl, L-arabinopyranosyl, D-arabinopyranosyl, D-xylopyranosyl, D-galactopyranosyl, D-mannopyranosyl or O- ⁇ -D-glucopyranosyl-(1 ⁇ 4)-D-glucopyranosyl
• A is straight or branched alkylene of two or three carbon atoms.
• a further preferred subgenus includes the compound of the formula [I] in which R 1 is alkoxy of one or two carbon atoms, R 2 is L-arabinopyranosyl, D-arabinopyranosyl or O- ⁇ -D-glucopyranosyl-(1 ⁇ 4)-D-glucopyranosyl, and A is ethylene, propylene, 1-methylethylene or 2-methylethylene.
• the nitrosourea compound [I] is prepared by nitrosation of a compound of the formula: ##STR3## wherein R 1 , R 2 and A are the same as defined above.
• the starting compound [II] is readily obtained.
• it can be prepared by condensing a primary amine of the formula: R 1 --A--NH 2 (wherein R 1 and A are the same as defined above) with a compound of the formula: R 2 --OH (wherein R 2 is the same as defined above) at about 20° to 80° C. in an inert solvent (e.g., methanol, ethanol) to give a secondary amine of the formula: ##STR4## (wherein R 1 , R 2 and A are the same as defined above), and then condensing said secondary amine with 2-chloroethyl isocyanate at 0° to 30° C. in an inert solvent (e.g., tetrahydrofuran, methanol, ethanol).
• an inert solvent e.g., tetrahydrofuran, methanol, ethanol
• the nitrosation of the invention is accomplished by contacting the compound [II] with nitrous acid, nitrogen trioxide or nitrogen tetroxide in an inert solvent.
• the reaction can be preferably carried out at a temperature of -20° to 20° C., especially at about 0° to about 5° C.
• Water, lower alkanols e.g., methanol, ethanol
• tetrahydrofuran methylene chloride
• ethyl acetate acetic acid
• formic acid are suitable examples of the inert solvents.
• free nitrous acid is prepared by reacting an alkali metal salt of nitrous acid (e.g., sodium nitrite, potassium nitrite) or a lower alkyl ester thereof (e.g., butyl nitrite, amyl nitrite) with a mineral or organic acid (e.g., hydrochloric acid, sulfuric acid, formic acid or acetic acid), it is preferred that said free nitrous acid is employed for subsequent nitrosation reaction immediately after preparation thereof.
• an alkali metal salt of nitrous acid e.g., sodium nitrite, potassium nitrite
• a lower alkyl ester thereof e.g., butyl nitrite, amyl nitrite
• a mineral or organic acid e.g., hydrochloric acid, sulfuric acid, formic acid or acetic acid
• nitrogen trioxide or nitrogen tetroxide when employed in the invention, it is preferred to carry out the nitrosation reaction by dissolving or suspending the starting compound [II] in the inert solvent and then introducing gaseous nitrogen trioxide or tetroxide thereto in the presence or absence of an acid acceptor.
• an acid acceptor Sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate are examples of suitable acid acceptors.
• the nitrosourea compound [I] thus obtained shows potent anti-tumor activity against various tumor cells such as Ehrlich's carcinoma, Sarcoma 180, Leukemia L-121:, Lewis lung carcinoma, Yoshida sarcoma and Rat ascites hepatoma. It may be useful to prolong the survival time of warm-blooded animals afflicted with said tumors and/or minimize the growth of said tumors in said animals. It may also be employed for therapy of malignant lymphoma, leukemia, stomach tumor and hepatoma in test animals. Effectiveness in human beings has not yet been demonstrated.
• the nitrosourea compound [I] can be used for pharmaceutical use in the form of a pharmaceutical preparation suitable for either oral or parenteral administration.
• the compound [I] may also be used in conjunction or admixture with a pharmaceutical excipient.
• the excipient selected must be the one which does not react with the compound [I]. Suitable excipients include, for example, gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talcum, vegetable oil and so forth. Other known medicinal excipients may be employed.
• the pharmaceutical preparation may be a solid dosage form such as, for example, a tablet, a coated tablet, a pill or a capsule; or a liquid dosage form such as, for example, a solution, a suspension or an emulsion. Further, the compound [I] may be employed, for example, in the form of an injection or suppository when administered parenterally.
• the pharmaceutical preparation may be sterilized and/or may contain auxiliaries such as, for example, preserving and stabilizing agents.
• the dose of the compound [I] for pharmaceutical use depends on route of administration; the age, weight and condition; and particular diseases to be treated. In general, it may be used for pharmaceutical use at a dose of 0.1 to 30 mg/kg, especially 0.2 to 10 mg/kg, per day.
• mice 10 5 leukemic cells of L-1210 were inoculated intraperitoneally into a group of four or six male mice (BDF 1 mice, body weight: 19-23 g).
• a test compound was dissolved in a physiological saline solution and administered intraperitoneally to the mice.
• the administration of the test compound was begun 24 hours after the inoculation of the leukemic cells and performed once a day for 5 days. The survival days of the treated mice were observed.
• CCNU 1-(2-chloroethyl)-1-nitroso-3-cyclohexylurea
• GANU 1-(2-chloroethyl)-1-nitroso-3-(D-glucopyranosyl)urea
• Example 1-(1) 7.2 g of D-maltose monohydrate, 2.7 g of 3-methoxy-n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as descrived in Example 1-(1), whereby 9.0 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-[O- ⁇ -D-glucopyranosyl-(1.fwdarw.4)-D-glucopyranosyl]urea (i.e., 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(D-maltosyl)urea) are obtained as colorless powder.
• 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(D-maltosyl)urea are obtained as colorless powder.
• the resultant oil is collected by decantation and then purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (2:1:1)), whereby 5.3 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are obtained as colorless caramel.
• Example 10-(2) 3.1 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-(D-xylopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2), whereby 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)-3-(D-xylopyranosyl)urea are obtained as yellow caramel.
• Example 10-(2) 3.6 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(D-glucopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2), whereby 2.7 g of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(D-glucopyranosyl)urea are obtained as yellow caramel.

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• 1979
  • 1979-08-14 NL NL7906191A patent/NL7906191A/nl not_active Application Discontinuation
  • 1979-08-14 US US06/066,421 patent/US4241053A/en not_active Expired - Lifetime
  • 1979-08-20 DE DE2933663A patent/DE2933663C2/de not_active Expired
  • 1979-08-21 IT IT25246/79A patent/IT1193213B/it active
  • 1979-08-23 FR FR7921268A patent/FR2434174A1/fr active Granted
  • 1979-08-23 CA CA000334307A patent/CA1121347A/en not_active Expired
  • 1979-08-24 GB GB7929525A patent/GB2031875B/en not_active Expired
  • 1979-08-24 AT AT0568979A patent/AT368517B/de not_active IP Right Cessation
  • 1979-08-24 CH CH773279A patent/CH640867A5/de not_active IP Right Cessation
  • 1979-08-24 ES ES483636A patent/ES483636A1/es not_active Expired

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